The long-term objective of the planned research is to understand the fundamental mechanisms underlying the pathological processes which occur in idiopathic Parkinson's Disease (PD). PD is a major degenerative brain disease estimated to affect at least 500,000 Americans and millions of individuals worldwide. The hallmark of PD is the degeneration of nigrostriatal dopamine (DA) neurons as a result of pathological processes of unknown origin which occur in the neuromelanin-pigmented cell bodies of these neurons located in the substantia nigra (SN) pars compacta. Based on many prior studies it appears that PD might develop as a consequence of two factors: (a) a genetically-inherited predisposition manifested by an impaired ability to detoxify and excrete environmental toxicants so that they can enter the brain; and, (b)chronic exposure to these substances. In view of the fact that selective dopaminergic neurotoxins have not been found in the environment, a new hypothesis is advanced which might contribute to an understanding of the fundamental pathoetiology of PD. It is proposed that in response to such a toxic brain insult the activity of nigral gamma-glutamyl transpeptidase is upregulated with the result that glutathione (GSH), synthesized and exported by glial cells, is translocated into the cytoplasm of SN cell bodies which normally contain little or none of this tripeptide. Because DAergic SN neurons possess a very weak antioxidant system, uniquely high levels of unsheltered DA, and high basal levels of DA autoxidation (they are pigmented with the end- product of this reaction, neuromelanin) the rise in cytoplasmic levels of GSH is proposed to cause a metabolic switch. This switch diverts the neuromelanin pathway and leads ultimately to the endogenous formation of aberrant dihydrobenzothiazine (DHBT) and benzothiazine (BT) metabolites. These are proposed to be the endotoxins which cause the death of SN neurons as a result of: (a) redox cycling reactions which generate elevated levels of cytotoxic reduced oxygen species evoking severe lipid peroxidation; and, (b) inhibition of mitochondrial complex I respiration. The specific aims of the project are: (l) to elucidate the oxidation chemistry of DA in the presence of GSM and L-cysteine under conditions which mimic those under which the proposed metabolic switch occurs; (2) to isolate and identify the major products of these reactions and determine their neurotoxicological, neuropharmacological and neurodegenerative properties using both in vivo and in vitro experiments; and, (3) to develop an experimental animal model which, in response to a chemical insult on the brain, exhibits the hypothesized GSH-mediated metabolic diversion in the SN. These investigations might ultimately lead to the development of a clinical assay for early diagnosis of PD and suggest therapeutic strategies to halt the degenerative processes.